This application claims priority under 35 U.S.C. xc2xa7119 (a)-(d) to Indian Provisional Patent Application Nos. 1018/DEL/2001 and 1019/DEL/2001, filed Oct. 1, 2001.
1. Field of the Invention
This invention in general relates to soluble and stable citrate salts of macrolides and processes for preparing, isolating and characterizing such salts and use thereof in all solid dosage forms of macrolides. In a preferred embodiment, the salts are used in oral controlled slow release solid pharmaceutical formulations, such as a once daily formulation of clarithromycin.
2. Description of the Related Art
The advantages of Controlled Release Dosage Forms for extended or sustained action are well known i.e. reduced daily dosage, patient convenience and improved patient compliance, especially in the case of very bitter-tasting drugs e.g. erythromycin and its derivatives. These macrolide antibiotics are known for their anti-bacterial activity against a number of micro-organisms and are typically administered as Immediate Release (IR) compositions, two or three times a day, for a regimen of 10 to 14 days. Clarithromycin, (6-O-methylerythromycinA) in particular, has a very bitter metallic taste which can result in poor compliance of the regimen or selection of another, possibly a less effective therapeutic agent.
An approach to address the possible non-compliance with the regimen is to develop controlled release solid preparations containing erythromycin derivatives. Unfortunately the properties of these macrolides, like many other poorly soluble basic drugs did not allow them to be incorporated in a single oral dosage form to provide a controlled efficient release of drug throughout a 24 hrs. period with reproducible bioavailability. The reason being that these erythromycin derivatives are slightly alkaline, practically water insoluble and acid-sensitive drugs. A basic drug""s solubility decreases with increasing pH as it proceeds distally towards the large intestine (pH 6 to 8), while it is soluble in stomach (pH 1.2) and upper or proximal region of small intestine (pH 5). Thus a poorly soluble basic drug will lead to less drug being available for absorption in lower or distal intestine. A daily dose of 500 mg of clarithromycin has to be incorporated in a relatively small matrix for the convenience of swallowing, thus leaving a relatively small space for the optimization of biopharmaceutical and physicochemical properties of a formulation. Consequently in the preparation of a 24 hrs. tablet, there arises the problem of high dose of poorly soluble clarithromycin along with the need to ensure its reproducible and pH independent release continuously from the dosage form as it proceeds through the GI tract.
U.S. Pat. No. 4,842,866 discloses the development of a controlled release formulation of erythromycin derivatives using an alginate matrix comprising a water soluble alginate and a complex salt of alginic acid, having one cation that yields a soluble alginate salt and another cation that alone yields an insoluble alginate salt. However, in vivo animal studies showed that reproducibly bioavailable controlled release formulations of macrolide antibiotics were not possible using alginates or any other monolithic hydrogel tablet due to their inherent problems of acid instability, poor drug solubility and variable and pH dependent GI transit. A major approach, which has been used since then to improve the bioavailability of erythromycin derivatives, is the use of an organic acid e.g. citric acid along with the poorly soluble basic drug in the form of physical mixture in a solid dosage form. This approach has been disclosed in Japanese Patent No. 163823 and this has been referred in the U.S. Pat. No. 5,705,190 and it has been believed that the formulation with the organic acid creates a micro-environment of low pH to enhance the solubility of the drug within the dosage form as it moves down the GI tract. Although the use of citric acid solved the problem of poor and variable GI absorption of macrolides, the problem of acid-instability still remained in these formulations as clarithromycin and free citric acid are in the vicinity of each other in these dosage forms. On one hand, clarithromycin, roxithromycin and other erythromycin derivatives are reported to be acid-sensitive drugs, while on the other hand, they are being used in direct contact with acids in these oral solid formulations.
An oral formulation containing a physical mixture of 6-0-methyl erythromycin A and citric acid with improved bioavailability has been disclosed in Japanese Patent No. 163823/1985.
U.S. Pat. No. 5,705,190 describes a solid oral pharmaceutical formulation with controlled release containing a drug poorly soluble in water, a water soluble alginate salt, a complex salt of alginic acid with a metal cation and an organic carboxylic acid facilitating the dissolution of the drug.
Japanese Patent No. 89/42,625 describes the preparation of film coated microgranules of a drug with sustained action, which in addition to clarithromycin also contain AEA and water.
International Publication No. WO 01/26663A1 describes a pharmaceutical formulation with extended action containing an erythromycin derivative and a hydrophilic water soluble polymer, showing at oral administration, an improved taste profile and fewer gastrointestinal side effects in comparison to the usual formulation.
International Publication No. WO 00/48607 describes an improved pharmaceutical formulation for controlled release of clarithromycin or its derivative, enabled by a novel combined matrix consisting of a fatty and a hydrophilic component, where to also a surfactant and a pH modulator may be added when an additional influence on the release profile of the active substance is desired.
International Publication No. WO 00/02567 describes water miscible pharmaceutical compositions containing up to about 40% of a macrolide such as an azalide antibiotic prepared by reaction of macrolide with acid in a non-aqueous water miscible organic solvent system.
International Publication No. WO 01/49246A2 covers the sustained release tablets containing Hydroxy Propyl Methyl Cellulose as Matrix material and clarithromycin as active ingredient.
Therefore there exists the need for developing a pharmaceutical composition of poorly soluble basic drugs, especially of macrolide antibiotics, which overcomes all their problems of poor solubility, pH-dependent solubility and irreproducible bioavailability, without having the problem of instability of drug due to the use of its physical mixture with citric acid. Also there exists a need to address two additional problems in controlled release dosage forms of macrolides i.e. (a) Slowing down of release of drug with aging from the mixture of citric acid and alginate matrix and (b) Non-Repeatable Dissolution Profiles of different batches of the above mentioned dosage form, as disclosed in Patent No. WO/00/48607.
The present application provides for a soluble and stable form of macrolide and its dosage forms thereof. In preferred embodiments, there are provided isolated citrate salts of macrolides in their oral controlled slow release solid formulations useful for reducing the daily dosage regimen and especially to a once daily formulation of clarithromycin.
In one embodiment, there is provided a controlled release pharmaceutical formulation comprising a macrolide citrate salt, at least one hydrophilic polymer, a binder, a filler and a lubricant, wherein the macrolide citrate salt is obtained by dispersing a macrolide in an organic solvent, adding an aqueous solution comprising an equimolar amount of citric acid to the macrolide, and evaporating the organic solvent.
In another embodiment, there is provided a method for producing a controlled release pharmaceutical formulation of macrolide citrate salt. The method comprises mixing multiple components comprising a macrolide citrate salt, a filler, and at least one hydrophilic polymer to form a first mixture of the multiple components, granulating the mixture in the presence of a binder to form granules which are dried, properly sized and lubricated to form an oral controlled release solid dosage formulation, wherein the granulating step is performed slowly, such that a solvent or a mixture of solvent and binder is added in small amounts to the first mixture. The method may further comprise compressing the lubricated granules to form a tablet and/or coating the oral controlled release solid dosage formulation.
The macrolide citrate salts according to preferred embodiments of formulations and methods are made by a method comprising dispersing a macrolide in an organic solvent, adding an aqueous solution comprising citric acid to the macrolide to form a mixture, and removing the organic solvent from the mixture to form a macrolide citrate salt, wherein the citric acid and macrolide are present in substantially equimolar quantities. The method may further comprise washing the macrolide citrate salt with cold water and drying the salt/evaporating the water. The methods may further comprise characterizing the isolated macrolide citrate salt by analyzing at least one property of the isolated citrate salt, such as assessing its melting point, assessing its stability, assessing its pH solubility, assessing its water content, assaying the salt by high performance liquid chromatography (HPLC) or assaying the salt by differential scanning calorimetry (DSC).
In preferred embodiments of the formulations and methods, the macrolide is clarithromycin or roxithromycin; the filler is selected from the group consisting of lactose, starches, glucose, sucrose, mannitol, and cellulose; at least one hydrophilic polymer is selected from the group consisting of povidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, and methacrylic acid copolymers; and/or the organic solvent is acetone. In preferred embodiments, the controlled release pharmaceutical formulation is in solid oral dosage form, such as a tablet, with a strength of 500 mg of clarithromycin, preferably adapted for a single dose regimen per day.
In a further embodiment, there is provided a pharmaceutical composition for the extended release of an erythromycin derivative in the gastrointestinal environment, comprising of the citrate salt of an erythromycin derivative, more particularly of clarithromycin, and a pharmaceutically acceptable polymer, so that its Dissolution Profile is equivalent to that of commercially available products and to that of a similar composition using physical mixture of drug and citric acid in place of the salt, with F2 values ranging from 63 to 67.